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Skin ulcers are most commonly due to circulatory or metabolic disorders and are a major public health concern. In developed countries, chronic wounds affect more than 1 % of the population and their incidence is expected to follow those observed for diabetes and obesity. In tropical and subtropical countries, an additional issue is the occurrence of ulcers of infectious origins with diverse etiologies. While the severity of cutaneous Leishmaniasis correlates with protective immune responses, Buruli ulcers caused by Mycobacterium ulcerans develop in the absence of major inflammation. Based on these two examples, this review aims to demonstrate how studies on microorganism-provoked wounds can provide insight into the molecular mechanisms controlling skin integrity. We highlight the potential interest of a mouse model of non-inflammatory skin ulceration caused by intradermal injection of mycolactone, an original lipid toxin with ulcerative and immunosuppressive properties produced by M. ulcerans.

Mycobacterium ulcerans disease (Buruli ulcer) is an important health problem in several west African countries. It is prevalent in scattered foci around the world, predominantly in riverine areas with a humid, hot climate. We review the epidemiology, bacteriology, transmission, immunology, pathology, diagnosis and treatment of infections. M. ulcerans is an ubiquitous micro-organism and is harboured by fish, snails, and water insects. The mode of transmission is unknown. Lesions are most common on exposed parts of the body, particularly on the limbs. Spontaneous healing may occur. Many patients in endemic areas present late with advanced, severe lesions. BCG vaccination yields a limited, relatively short-lived, immune protection. Recommended treatment consists of surgical debridement, followed by skin grafting if necessary. Many patients have functional limitations after healing. Better understanding of disease transmission and pathogenesis is needed for improved control and prevention of Buruli ulcer.

Buruli ulcer (BU) is an emerging infectious disease that causes disfiguring skin ulcers. The causative agent, Mycobacterium ulcerans , secretes toxin called mycolactone that triggers inflammation and immunopathology. Existing treatments are lengthy and consist of drugs developed for tuberculosis. Here, we report that a pyrazolo[1,5-a]pyridine-3-carboxamide, TB47, is highly bactericidal against M. ulcerans both in vitro and in vivo. In the validated mouse model of BU, TB47 alone reduces M. ulcerans burden in mouse footpads by more than 2.5 log 10 CFU compared to the standard BU treatment regimen recommended by the WHO. We show that mutations of ubiquinol-cytochrome C reductase cytochrome subunit B confer resistance to TB47 and the dissimilarity of CydABs from different mycobacteria may account for their differences in susceptibility to TB47. TB47 is highly potent against M. ulcerans and possesses desirable pharmacological attributes and low toxicity that warrant further assessment of this agent for treatment of BU. Combination therapy for Buruli ulcer (BU) is suboptimal. Here, Liu et al. show that the candidate drug TB47 has potent bactericidal activity against Mycobacterium ulcerans in vitro and in a mouse model, which underscores its potential for shortening the course of BU and treating other mycobacterial diseases.

Key Points Buruli ulcer is an emerging human disease associated with watercourses. It is especially prevalent in West African countries, such as Ghana or Benin, but also occurs in parts of Australia. Buruli ulcer results from infection with Mycobacterium ulcerans , a slow-growing toxin producer that is found in aquatic habitats. There is growing evidence to suggest that insects can act as vectors, as M. ulcerans has been found in water bugs, water striders and mosquitoes, although this is still controversial. M. ulcerans is a descendant of the ubiquitous fast-growing Mycobacterium marinum , which has undergone reductive evolution, gene decay and genome downsizing, probably after horizontal acquisition of a virulence plasmid. The virulence plasmid carries genes for huge polyketide synthases: assembly line enzymes that produce a macrolide toxin with multiple activities that is known as mycolactone. Mycolactone is cytotoxic and has immunosuppressive properties for professional antigen-presenting cells. It prevents dendritic cells from priming cellular immune responses and producing the chemotactic signals that are crucial for inflammation. Humans contract Buruli ulcer following infection with Mycobacterium ulcerans , a slow-growing toxin producer that evolved from Mycobacterium marinum . Both M. ulcerans and M. marinum are waterborne, but M. ulcerans is associated with various insects that might serve as vectors. This Review summarizes recent findings and explains how the toxin, a polyketide called mycolactone, acts on immune cells. Buruli ulcer is an emerging human disease caused by infection with a slow-growing pathogen, Mycobacterium ulcerans , that produces mycolactone, a cytotoxin with immunomodulatory properties. The disease is associated with wetlands in certain tropical countries, and evidence for a role of insects in transmission of this pathogen is growing. Comparative genomic analysis has revealed that M. ulcerans arose from Mycobacterium marinum , a ubiquitous fast-growing aquatic species, by horizontal transfer of a virulence plasmid that carries a cluster of genes for mycolactone production, followed by reductive evolution. Here, the ecology, microbiology, evolutionary genomics and immunopathology of Buruli ulcer are reviewed.

Summary Infection of subcutaneous tissue with Mycobacterium ulcerans can lead to chronic skin ulceration known as Buruli ulcer. The pathogenesis of this neglected tropical disease is dependent on a lipid‐like toxin, mycolactone, which diffuses through tissue away from the infecting organisms. Since its identification in 1999, this molecule has been intensely studied to elucidate its cytotoxic and immunosuppressive properties. Two recent major advances identifying the underlying molecular targets for mycolactone have been described. First, it can target scaffolding proteins (such as Wiskott Aldrich Syndrome Protein), which control actin dynamics in adherent cells and therefore lead to detachment and cell death by anoikis. Second, it prevents the co‐translational translocation (and therefore production) of many proteins that pass through the endoplasmic reticulum for secretion or placement in cell membranes. These pleiotropic effects underpin the range of cell‐specific functional defects in immune and other cells that contact mycolactone during infection. The dose and duration of mycolactone exposure for these different cells explains tissue necrosis and the paucity of immune cells in the ulcers. This review discusses recent advances in the field, revisits older findings in this context and highlights current developments in structure‐function studies as well as methodology that make mycolactone a promising diagnostic biomarker.

Infection with Mycobacterium ulcerans is characterised by tissue necrosis and immunosuppression due to mycolactone, the necessary and sufficient virulence factor for Buruli ulcer disease pathology. Many of its effects are known to involve down-regulation of specific proteins implicated in important cellular processes, such as immune responses and cell adhesion. We have previously shown mycolactone completely blocks the production of LPS-dependent proinflammatory mediators post-transcriptionally. Using polysome profiling we now demonstrate conclusively that mycolactone does not prevent translation of TNF, IL-6 and Cox-2 mRNAs in macrophages. Instead, it inhibits the production of these, along with nearly all other (induced and constitutive) proteins that transit through the ER. This is due to a blockade of protein translocation and subsequent degradation of aberrantly located protein. Several lines of evidence support this transformative explanation of mycolactone function. First, cellular TNF and Cox-2 can be once more detected if the action of the 26S proteasome is inhibited concurrently. Second, restored protein is found in the cytosol, indicating an inability to translocate. Third, in vitro translation assays show mycolactone prevents the translocation of TNF and other proteins into the ER. This is specific as the insertion of tail-anchored proteins into the ER is unaffected showing that the ER remains structurally intact. Fourth, metabolic labelling reveals a near-complete loss of glycosylated and secreted proteins from treated cells, whereas cytosolic proteins are unaffected. Notably, the profound lack of glycosylated and secreted protein production is apparent in a range of different disease-relevant cell types. These studies provide a new mechanism underlying mycolactone's observed pathological activities both in vitro and in vivo. Mycolactone-dependent inhibition of protein translocation into the ER not only explains the deficit of innate cytokines, but also the loss of membrane receptors, adhesion molecules and T-cell cytokines that drive the aetiology of Buruli ulcer.

Buruli ulcer (BU) is an infection of subcutaneous tissue caused by Mycobacterium ulcerans . This bacterial infection affects the lives of thousands of people each year across West and Central Africa and Australia. Recent research showed that as few as 2–3 M. ulcerans are sufficient to cause infection. Unfortunately, earlier laboratory studies have used unrealistically high bacterial doses to test new vaccines or to understand host responses, compromising subsequent conclusions. This research is significant because it takes a fresh approach to develop an experimental animal infection model for BU that uses a carefully calibrated and realistic infectious dose. The findings from assessing this new infection model are the foundation for an ambitious new program to develop a controlled human infection model for M. ulcerans , a platform for developing new therapies to prevent and treat BU.

Buruli ulcer (BU) is a necrotizing disease of skin and soft tissue caused by the bacterium Mycobacterium ulcerans (MU). In Australia, where the disease is emerging in new geographic areas and human case numbers are increasing, native possum species act as reservoir hosts. To better understand the life history of MU in one of its natural hosts, we conducted intra-dermal challenge of six wild caught, MU-naïve common ringtail possums ( Pseudocheirus peregrinus ). All six animals developed BU disease consistent with that observed in naturally infected ringtail possums. Time to ulceration varied between 49 and 77 days (mean = 61.8 days). Molecular evidence of systemic infection was detected in five animals and was supported by consistent histopathological findings in four animals. Pathological findings included random, multifocal, granulomatous hepatitis in four possums, one of which also had a mild, multifocal, interstitial granulomatous pneumonia. Acid-fast bacilli were only evident in inflammatory foci beyond the primary inoculation site in one possum. The ringtail possum model of MU infection is an important tool for the investigation of bacterial transmission dynamics, pathogenesis and immune response in a natural host. Data from this model may improve disease risk modelling and help identify intervention points to stop zoonotic transmission and disease spread.

The role of biofilms in the pathogenesis of mycobacterial diseases remains largely unknown. Mycobacterium ulcerans, the etiological agent of Buruli ulcer, a disfiguring disease in humans, adopts a biofilm-like structure in vitro and in vivo, displaying an abundant extracellular matrix (ECM) that harbors vesicles. The composition and structure of the ECM differs from that of the classical matrix found in other bacterial biofilms. More than 80 proteins are present within this extracellular compartment and appear to be involved in stress responses, respiration, and intermediary metabolism. In addition to a large amount of carbohydrates and lipids, ECM is the reservoir of the polyketide toxin mycolactone, the sole virulence factor of M. ulcerans identified to date, and purified vesicles extracted from ECM are highly cytotoxic. ECM confers to the mycobacterium increased resistance to antimicrobial agents, and enhances colonization of insect vectors and mammalian hosts. The results of this study support a model whereby biofilm changes confer selective advantages to M. ulcerans in colonizing various ecological niches successfully, with repercussions for Buruli ulcer pathogenesis.

Pathogens such as bacteria, fungi and viruses are important components of soil and aquatic communities, where they can benefit from decaying and living organic matter, and may opportunistically infect human and animal hosts. One-third of human infectious diseases is constituted by sapronotic disease agents that are natural inhabitants of soil or aquatic ecosystems. They are capable of existing and reproducing in the environment outside of the host for extended periods of time. However, as ecological research on sapronosis is infrequent and epidemiological models are even rarer, very little information is currently available. Their importance is overlooked in medical and veterinary research, as well as the relationships between free environmental forms and those that are pathogenic. Here, using dynamical models in realistic aquatic metacommunity systems, we analyze sapronosis transmission, using the human pathogen Mycobacterium ulcerans that is responsible for Buruli ulcer. We show that the persistence of bacilli in aquatic ecosystems is driven by a seasonal upstream supply, and that the attachment and development of cells to aquatic living forms is essential for such pathogen persistence and population dynamics. Our work constitutes the first set of metacommunity models of sapronotic disease transmission, and is highly flexible for adaptation to other types of sapronosis. The importance of sapronotic agents on animal and human disease burden needs better understanding and new models of sapronosis disease ecology to guide the management and prevention of this important group of pathogens.